Physiologic concentrations of exogenously infused ghrelin reduces insulin secretion without affecting insulin sensitivity in healthy humans.

Background: Infusion of ghrelin to supraphysiologic levels inhibits glucose-stimulated insulin secretion, reduces insulin sensitivity, and worsens glucose tolerance in humans.

Objective: The purpose of this study was to determine the effects of lower doses of ghrelin on insulin secretion and insulin sensitivity in healthy men and women.

Methods: Acyl ghrelin (0.2 and 0.6 nmol kg(-1) h(-1)) or saline was infused for 225 minutes in 16 healthy subjects on 3 separate occasions in randomized order. An i.v. glucose tolerance test was performed, and the insulin sensitivity index (SI) was derived from the minimal model. Insulin secretion was measured as the acute insulin response to glucose (AIRg) and the disposition index was computed as AIRg × SI.

Results: Ghrelin infusions at 0.2 and 0.6 nmol kg(-1) h(-1) raised steady-state plasma total ghrelin levels 2.2- and 6.1-fold above fasting concentrations. Neither dose of ghrelin altered fasting plasma insulin, glucose, or SI, but both doses reduced insulin secretion compared with the saline control, computed either as AIRg (384 ± 75 and 354 ± 65 vs 520 ± 110 pM · min [mean ± SEM], respectively; P < .01 for both low- and high-dose vs saline) or disposition index (2238 ± 421 and 2067 ± 396 vs 3339 ± 705, respectively; P < .02 for both comparisons). The high-dose ghrelin infusion also decreased glucose tolerance.

Conclusions: Ghrelin infused to levels occurring in physiologic states such as starvation decreases insulin secretion without affecting insulin sensitivity. These findings are consistent with a role for endogenous ghrelin in the regulation of insulin secretion and suggest that ghrelin antagonism could improve β-cell function.